Many nonpeptide, C-2 symmetric and pseudosymmetric compounds have shown good biological activity as HIV protease inhibitors. Compounds and methods for their preparation are increasingly found in the literature: (Kempf, D. et al., J. Org. Chem. 57 5692-5700 (1992); Livermore, D. et al., J Med Chem, 36 3784-3794 (1993); Lam, P., et al., Science 263 380-384 (1994); European Patent EP 402,646; Dreyer et al., Biochemistry 32(3) 937-47 (1993); Jadhav et al, Bioorganic & Med. Chem. Lett 2(4) 353-356 (1992); Jadhav et al., U.S. Pat. No. 5,294,720, issued Mar. 15, 1994).
Seebach has demonstrated that the seven membered ring acetal, trioxepane, is a useful protecting group for tartaric acid (Seebach, D. et al., Chimia, 45 (7/8) 238-244 (1991)).
Baker and Condon, J. Org. Chem. 58, 3277-3284 (1993), disclose a method for the preparation of linear diaminodiols from (-)-2,3-O-isopropylidene-D-threitol. Cyclization of the linear diol is not taught. ##STR2##
Copending commonly assigned patent application U.S. Ser. No. 08/047330, filed Apr. 15, 1993, discloses a process for the synthesis of cyclic ureas, as shown below, wherein at least one of R.sup.22 and R.sup.23 are hydrogen, useful as HIV-1 protease inhibitors. The analogous groups R.sup.5, R.sup.5a and R.sup.6, R.sup.6a can be taken together to form a ketal ring. As well they can be taken separately and can be 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), triethylsilyl (TES), or 2-(trimethylsilyl)ethoxymethyl (SEM) protected hydroxyls. ##STR3## The claimed process comprises contacting a compound of the formula: ##STR4## with a suitable cyclizing reagent in a suitable solvent, said solvent optionally containing a base, thereby to form the cyclic compound. The hydroxyl protecting groups taught in that process are less advantageous than the trioxepane protecting group of the present invention.
Acetonide has been used to protect the diol function in the preparation of linear HIV protease inhibitors (Baker, W. et al., J. Org. Chem. 58, 3277-3284 (1993); Baker, W. et al., Tetrahedron Lett. 33, 1581-1584 (1992)).
Each method described above utilizes expensive amino acid or saccharide as a source of chiral starting materials. Each method described above requires chromatographic purification of the products. The expense of the starting materials and the requirement of performing chromatography to purify reaction products renders the above-described methods undesirable for large scale production of HIV protease inhibitors.
There is a need for an efficient method for the preparation of HIV protease inhibitors that uses inexpensive chiral starting materials such as tartaric acid, and which does not require chromatography.